Preterm labor is the major cause of prenatal morbidity and mortality in the United States. Current methods of inhibiting preterm labor are not always successful and are often associated with significant side effects. Since the uterus is a target organ for oxytocin, and assuming that oxytocin is an important contributing factor to preterm labor, the development of a potent oxytocin antagonist would result in successful inhibition of preterm labor with few associated side effects.
Structurally, oxytocin (OT) and antidiuretic hormone (ADH), also called vasopressin, are similar. Their comparative structures are illustrated below. ##STR1##
Various investigations in the literature have reported the synthesis of antagonists to ADH for the treatment of hypertension and the synthesis of antagonists to oxytocin. In 1960, Law, H. D. and V. DuVigneaud, J. Am. Chem. Soc., 82:4579, reported the first synthesis of an oxytocin antagonist (2-0-methyltyrosine-OT). In 1967, Chan, Fear and DuVigneaud, Endocrinology, 81:1267, reported the synthesis of 1-L-Penicillamine-oxytocin and 1-deaminopenicillamine-oxytocin. This was the first study to show an in vivo inhibitory effect of an oxytocin antagonist on uterine contractions and response to oxytocin in the anesthetized rat.
In 1980, Sawyer, et al., Endocrinology, 106:81, reported the synthesis of an oxytocin antagonist that combined the two important features of the antagonist of Law and DuVigneaud and of the antagonist of Chan, et al. The new antagonist was (1-deaminopenicillamine, 2-0-methyltyrosine) oxytocin. The new antagonist had a pA.sub.2 of 7.8 as determined by the oxytocic bioassay. The pA.sub.2 is the negative logarithm of the molar concentration of the antagonist that reduces the response to the antagonist by 1/2. It is defined by Schild, British J. Pharmacology, 26:189 (1947).
In 1983, Manning, et al., J. Med. Chem., 26:1607-161 reported the synthesis of a number of antagonists to ADH. One of these antagonists proved to have potential anti-oxytocic activity [.beta.,.beta.-pentamethylene-.beta.-mercaptopropionic acid.sup.1,D-Phe.sup.2,Ile.sup.4 ] arginine vasopressin with a pA.sub.2 of 8.2, or in other words, 2.5 times more potent than the antagonist reported by Sawyer, et al. in 1980 (see page 1610, Table I, compound no. 1). This oxytocin antagonist can be called [Pmp.sup.1,D-Phe.sup.2, Phe.sup.3, Ile.sup.4, Arg.sup.8 ] oxytocin. A related oxytocin antagonist, [Pmp.sup.1, D-Trp.sup.2, Phe.sup.3, Ile.sup.4, Arg.sup.8 ] oxytocin was disclosed by Wilson and Flouret, Abstract for Society for the Study of Reproduction Meeting Jul. 14-17, 1986.
In 1981, Melin, et al., Endocrinology, 88:173, developed an oxytocin antagonist for inhibiting preterm labor. They synthesized 1-deamino, ethyloxytocin which had a pA.sub.2 of 7.2. They also showed that this compound inhibited uterine contractions in rats in vivo and in humans in vitro and in vivo (Akerland, et al., Obstet. and Gynecol., 62:309, 1983). In 1985, Akerland, et al., Obstet. and Gynecol. Scand., 64:499, reported the synthesis of 1deamino[D-Tyr(OEt).sup.2, Thr.sup.4, Orn.sup.8 ] vasopressin with a pA.sub.2 of 8.3. They have tested this compound in vitro on human uterine tissue and have shown it to inhibit uterine contractions.
U.S. Pat. No. 4,597,901 discloses the class of vasopressin antagonists in which cysteine-1 is present in both oxytocin and vasopressin and substituted with .beta.,.beta.-cylopentamethylene-.beta.-mercaptopropionic acid.
Other amino acids of vasopressin are substituted. The resulting class of compounds is said to be vasopressin antagonists the biological activity being manifested as water diuresis.